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Bioorg Med Chem Lett ; 24(3): 870-9, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24405701

ABSTRACT

Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 µM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.


Subject(s)
Mycobacterium tuberculosis/drug effects , Pyridones/chemical synthesis , Thiazoles/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Urea/chemical synthesis , Urea/pharmacology , Administration, Oral , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Disease Models, Animal , Inhibitory Concentration 50 , Mice , Microbial Sensitivity Tests , Molecular Structure , Pyridones/chemistry , Pyridones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Topoisomerase II Inhibitors/chemistry , Urea/chemistry
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